In our continuing effort to tackle the problem of ill-defined phenotypes we examined the contribution of several potentially functional variants in the genes (COMT, AKT1, and DISC1) each are associated with risk of schizophrenia (SCZ) and impact cognitive function. Working memory (WM) is critically mediated by dopaminergic tuning of signal-to-noise in cortical neural assemblies. Here, we used the COMT val158met genotype as an index of relative cortical dopamine bioavailability and tuning efficiency to examine the spatial and subprocess specificity by which dopaminergic modulation occurs within the prefrontal-parietal-striatal network during WM, thus empirically showing that dopamine plays a key role in updating and stabilizing new information at the neural systems level. We found that temporal updating operations, engaged relatively specific dopaminergic tuning at the DLPFC. Manipulating and rapidly updating representations were sensitive to dopaminergic modulation of neural signaling in a larger prefrontal-parietal-striatal network. These findings add to the integration of dopaminergic signaling in basic cortical assemblies with their roles in specific human brain networks during the orchestration of information processing in working memory. In the case of AKT1, AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. We provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopamine function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with AKT1 variation. Neuroimaging measures show a main affect of the AKT1 genotype, with significant epistasis with the functional COMT val158met mutation. This genetic interaction was consistent with the putative role AKT1 in dopaminergic signaling. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis. Ser704Cys DISC1 has been associated with SCZ and with specific hippocampal abnormalities. We investigated the Ser704Cys DISC1 mutation with in vivo brain phenotype including hippocampal formation gray matter volume, HF function and HF functional coupling with the neural network engaged during encoding of recognition memory. Ser/ser subjects showed greater gray matter volume in HF and greater involvement of the HF with increased HF-DLPFC coupling during memory encoding. The Ser704Cys DISC1 mutation is physiologically important and our findings support the hypothesis that genetic variation in DISC1 may affect risk for SCZ by modifying hippocampal gray matter and function. Our last study looked at the effect of BDNF val66met on measures of N-acetyl-aspartate (NAA) containing compounds. The BDNF val/met substitution does not affect BDNF protein function, it impacts the regulated secretion of the mature peptide by altering intracellular trafficking and protein packaging. Val/met subjects exhibited significantly reduced levels of left hippocampal NAA/CRE and NAA/CHO compared with val/val subjects. This effect was independent of age, IQ, number of voxels, hippocampal volume, or grey matter content in the area of interest. We confirm previous studies that the association between the BDNF-met variant and reduced levels of hippocampal NAA found in a similar technique. This study adds to the evidence that the BDNF val/met genotype affects hippocampal biology with implications for a variety of neuropsychiatric disorders[unreadable] [unreadable] We have also examined gene-gene interaction in dopamine regulating genes, COMT and DAT, as well as BDNF and SLC6A4. We investigated the effect of genetic variation of dopamine inactivation via COMT and dopamine transporter (DAT) on hippocampal activity in HC during different memory conditions. Our results consistently demonstrated a double dissociation so the DAT 9-repeat alleles modulated activity in the hippocampus in the exact opposite direction of DAT10/10-repeat alleles based on COMT val158met genotype during different memory conditions. Similar results were evident in ventrolateral and DLPFC. Our data also demonstrate in human brain, interaction of two genes implicated in dopamine signaling on brain activity during different memory conditions. We also examined the genetic interaction of serotonin transporter, SLC6A4, and BDNF gene. BDNF met allele protects against the serotonin short allele-induced effects on brain circuitry involving the amygdala and the subgenual portion of the anterior cingulate. To our knowledge, these are the first data showing biologic epistasis between BDNF and serotonin genes in vivo in the human brain in the context of depression and anxiety.[unreadable] [unreadable] We studied brain structural alterations in patients with schizophrenia. Shared neuropathological characteristics of SCZ and their sibs might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. Currently available data on the heritability of these structural changes are inconsistent. SCZ showed bilateral decrease in hippocampal and cortical gray matter volume and increases in bilateral dorsal striatum in right lateral ventricle compared with HC. No significant volumetric differences were found in unaffected sibs compared with HC in any structure. Additional exploratory analyses were performed on amygdala, thalamus, nucleus accumbens, ventral diencephalon, and cerebral and cerebellar cortex and white matter. Of these regions, SCZ showed increased volume in ventral diencephalon and cerebellum. These findings support evidence of genetic control of brain volume even in adults, particularly of hippocampal and neocortical volume and of cortical volumetric reductions being familial, but do not support measures of subcortical volumes as representing intermediate biologic phenotypes. We also sought to discover previously unidentified gray matter volume differences in SCZ and sibs with optimized voxel-based morphometry. We found that SCZ had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with HC. The unaffected sibs tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of sibs with a past history of mood disorder. Although sibs might share some regional gray matter decreases with their affected sibs, the pattern of regional differences might be a weak intermediate phenotype of SCZ.[unreadable] [unreadable] Lastly, we investigated proteins involved in cognitive aging with the hope that this would facilitate the development of novel treatments to combat cognitive impairment. It is likely with early identification of susceptible individuals, early intervention through life-style changes and other methods could increase an individual's resilience to the effects of aging.